PROJECT SUMMARY/ABSTRACT Approximately 6.3 million fractures occur in the United States each year, accounting for 16% of all musculoskeletal injuries and leading to well over 10 million hospital and physician offices visits. Up to 10% of fractures are recalcitrant and require surgical intervention for proper healing. The weakened bones in the growing geriatric population are contributing to the rising number of cases of this orthopedic problem and are projected to fuel demand for new, innovative solutions. According to the Department of Economic and Social Affairs, United Nations, Population Division, the number of people aged over 60 was 841 million in 2013 and is expected to reach 2 billion in 2050. Thus, the market is anticipated to witness a significant demand in coming decades. Cayman Chemical Company, Inc. seeks to address the unmet need by developing and commercializing a new small molecule based locally-administered drug-matrix combination for at-risk elderly fracture patients with delayed or nonunion fractures (DNFs). Cayman had discovered and patented a series of EP4 receptor agonists designed, synthesized, and screened for target potency and selectivity, cell activity, and metabolic and physicochemical properties amenable to rapid systemic clearance suitable for local administration. During Phase I of this project, Cayman selected the lead compound, KMN-159, that demonstrated osteogenic capacity in vitro and will serve as the active pharmaceutical ingredient (API) in the combination product. An osteoconductive mineralized collagen matrix (MCM) was functionalized with multiple doses of KMN-159, and the combination was evaluated in an accepted young rat femoral critical size defect model of nonunion fracture, demonstrating dose-dependent efficacy. During Phase II, Cayman will demonstrate dose-dependent efficacy of the combination in a model comparable to that used in the pilot study using young and old rats from the NIA rodent colony. Cayman will also initiate cGMP development of the API manufacture process, with which it will produce the release API batch that will be used for a GLP-compliant pivotal rabbit study. Cayman will combine the released API with a commercial 510(k)-approved MCM and demonstrate efficacy and safety in the GLP rabbit study.